CN109069824B - Treatment of autoimmune diseases using deep brain stimulation - Google Patents

Abstract

Techniques for treating autoimmune diseases using electrical stimulation through an implantable pulse generator and at least one electrode. An electrode lead is surgically implanted in the region of the islet cortex to deliver electrical stimulation. The at least one electrode lead and the implantable pulse generator include features that allow electrical stimulation to be directed to specific volumes of the islet cortex and ensure that non-treatment volumes do not receive electrical stimulation.

Description

Treatment of autoimmune diseases using deep brain stimulation

Cross Reference to Related Applications

This application claims benefit and priority from U.S. provisional patent application No. 62/290,101 filed on 2.2.2016. The contents of the above application are incorporated herein in their entirety by reference.

Background

For autoimmune diseases, the immune system is directed to the body's endogenous structures. When not properly inhibited by regulatory T-cells, T-cells may play a role in recognizing endogenous structures as foreign to the body. The reason for the failure of regulatory T-cells to regulate T-cells may not be known. Loss of regulation can lead to inflammatory responses at both the humoral and cellular levels, which are dependent on the entity of the autoimmune disease, which can lead to injury to various organs.

Disclosure of Invention

The present disclosure discusses electrical stimulation of the brain using electrodes attached to an implantable pulse generator. In some embodiments, the systems described herein use electrical stimulation to treat autoimmune diseases, such as rheumatoid arthritis and Crohn's disease. Treatment is performed by an implantable pulse generator attached to at least one electrode lead. An electrode lead is surgically implanted in or near a brain target (target) associated with a pathological condition. Neural tissue near the distal end of the electrode lead may be stimulated with electrical signals sent from the implantable pulse generator. The electrical stimulation may be performed continuously or intermittently. In some embodiments, the electrode guide is segmented to provide a directional electrode. The orientation electrode may orient the electrical stimulation toward a predetermined neural target. Targeting of the electrical stimulation may reduce side effects caused by the electrical stimulation. In some embodiments, the electrode guide may also be used to record signals from brain anatomy (anatomi). The recorded signals can be analyzed to indicate an autoimmune disease, and brain anatomy can then be stimulated to alleviate symptoms of the autoimmune disease.

According to one aspect of the present disclosure, a method of treating an autoimmune disease includes implanting an implantable stimulator (stimulator) in a patient. The method may include implanting an electrode lead in a patient. The electrode lead may include a MEMS membrane. The MEMS membrane may include a plurality of electrodes, a plurality of peripheral traces (circumferential traces) at least partially surrounding each of the plurality of electrodes, and at least two connection points coupling (coupling) each of the plurality of peripheral traces with a respective one of the plurality of electrodes. The method may include driving an electrode guide toward a first target location in a brain of a patient. The first target location may comprise one of a first, second, third or fourth gyrus of the anterior island cortex (organ insulating cortex); superior-anterior cerebral island (super-organ insula); inferior-anterior cerebral island (affeior-organ sula); anterior-anterior cerebral island (antigen-antigen islands); posterior-anterior cerebral island (spatial-organ island); large islet gyrus of hindbrain island; superior-posterior cerebral island (super-temporal island); or inferior-posterior cerebral island (afferior-posteror insula). The method may include generating an electrical signal by an implantable stimulator. The method may include delivering an electrical signal to a first target location via at least one of a plurality of electrodes.

The method can include treating an autoimmune disease with an electrical signal. Autoimmune diseases may include rheumatoid arthritis; psoriasis; psoriatic arthritis; spondyloarthritis; collagen diseases; vasculitis; guillain-barre syndrome; crohn's disease (morbus chrohn); ulcerative colitis; igg 4-related diseases; osteoarthritis; fibromyalgia; and Marangsie's syndrome.

The method may include driving a second guide relative to the first target position toward a second target position located on a contralateral side of the patient. At least one of the plurality of electrodes may be a directional electrode. The method may include recording neural activity from a target location, and selecting a portion of the plurality of electrodes to deliver an electrical signal based on the recorded neural activity.

The method may include detecting the presence of an autoimmune disease condition, and increasing the characteristics of the electrical signal. The electrical signal may be characterized by at least one of amplitude, frequency, and pulse width. The method may include detecting the presence of a side effect caused at least in part by the electrical signal and reducing a characteristic of the electrical signal.

The method may include determining that neural activity of the target region is below a predetermined threshold and applying an electrical stimulus having a frequency of about 120Hz to about 140 Hz. The method may include determining that neural activity of the target region is above a predetermined threshold, and applying an electrical stimulus having a frequency of about 40Hz to about 60 Hz.

At least one of the plurality of electrodes may be an omni-directional electrode. The omnidirectional electrode may be a recording electrode. The MEMS membrane may include a ribbon cable (ribbon cable) extending from a distal end of the MEMS membrane and into a lumen defined by the MEMS membrane. The ribbon cable may include a plurality of contact pads. Each of the plurality of peripheral traces may be coupled to one of the plurality of contact pads. Each of the plurality of electrodes may include a second metal layer. The second metal layer may include at least one of platinum, iridium oxide (iridium oxide), or titanium.

The method may include generating an electrical signal having a frequency of about 2Hz to about 500 Hz. The method can include generating an electrical signal having a pulse width of about 10 μ s to about 500 μ s. The method may include generating an electrical signal having a current of about 0.1mA to about 12 mA. The method may include selecting a different electrode of at least one of the plurality of electrodes to deliver the electrical signal. The method may include delivering an electrical signal to a first target location via a different electrode of at least one of the plurality of electrodes.

Drawings

The drawings described herein are for illustration purposes. In some instances, aspects of the described implementations may be shown exaggerated or enlarged to facilitate an understanding of the described implementations. In the drawings, like reference numbers generally indicate identical, functionally similar, and/or structurally similar elements throughout the several views. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the present teachings. The drawings are not intended to limit the scope of the present teachings. These systems and methods may be better understood from the following exemplary description with reference to the following drawings, in which:

fig. 1 illustrates an example system for treating autoimmune disease.

Fig. 2 illustrates an example electrode guide for the system illustrated in fig. 1.

Fig. 3A-3C illustrate the distal end of an electrode lead for the system illustrated in fig. 1.

Fig. 4A and 4B illustrate the distal end of an electrode guide for the system illustrated in fig. 1.

Fig. 4C-4E illustrate MEMS membranes with electrodes of redundant peripheral traces for the system illustrated in fig. 1.

Fig. 5 illustrates a block diagram of the components of an implantable pulse generator for the system illustrated in fig. 1.

Fig. 6 illustrates a flow chart of a method of tuning (tuning) electrical stimulation delivered to a patient using the system illustrated in fig. 1.

Fig. 7 illustrates a partial cross-sectional view of a human brain.

FIG. 8 is a block diagram of an example island cortex.

Figure 9A illustrates a position through a sagittal section plane of a patient.

Figure 9B illustrates a Magnetic Resonance Imaging (MRI) image at the sagittal section illustrated in figure 9A.

Fig. 10A illustrates the position of the horizontal slice plane through the (through) patient.

Fig. 10B illustrates an MRI image at the horizontal section illustrated in fig. 10A.

Fig. 11A illustrates the position of the coronal slice plane through the patient.

FIG. 11B illustrates an MRI image at the coronal suture section illustrated in FIG. 11A.

Fig. 12A illustrates a position through a sagittal section plane of a patient.

Fig. 12B illustrates an MRI image at the sagittal section illustrated in fig. 12A.

FIG. 13 illustrates an example left side guide vane cortex and an example right side guide vane cortex.

Fig. 14 illustrates a Computed Tomography (CT) image of the skull of a female patient with right part-medium occlusion.

Fig. 15 illustrates a cranial MRI image of the same female patient, with a CT image illustrated in fig. 14.

Fig. 16 illustrates a scintigraphic image of the hand of the female patient illustrated in fig. 14 and 15.

Figures 17 and 18 illustrate x-rays from the hand of a 68 year old female patient with right sided paralysis since birth.

Figures 19-23 illustrate x-ray images of patients with symmetrical progressive psoriatic arthritis over the last few years.

Fig. 24 and 25 illustrate an example atlas of stereotactic surgery of the human brain.

Detailed Description

The various concepts introduced above and discussed in greater detail below may be implemented in any of numerous ways, as the described concepts are not limited to any particular implementation. Examples of specific implementations and applications are provided primarily for illustrative purposes.

Fig. 1 illustrates an example system 101 for treating autoimmune and other diseases. The system 101 includes an Implantable Pulse Generator (IPG)110 implanted in the chest of the patient 100. The IPG 110 may be implanted under the collarbone or other region of the patient. An extension cable 120 couples the IPG 110 to the electrode guide 130. A plurality of electrode leads 130 (each coupled to the IPG 110 by an extension cable 120) may be implanted in the patient 100. As shown, the electrode lead 130 is implanted in the brain 140 of the patient 100.

The system 101 may include an IPG 110. The IPG 110 is configured to generate electrical signals that are transferred to the target tissue via the extension cable 120 and the electrode guide 130. In some embodiments, the IPG 110 is further configured to record electrical activity generated by the brain target and detected by the electrode lead 130. The IPG 110 may be configured to provide a series of electrical signals to a target tissue (e.g., brain 140) by adjusting a pulse frequency, a pulse width, a pulse amplitude, or any combination thereof. The IPG 110 may generate a pulse frequency range of about 2Hz to about 1kHz, about 2Hz to about 500Hz, or about 2Hz to about 250 Hz. In some embodiments, the IPG 110 is configured to stimulate neural activity at a brain target (also referred to as increasing neural activity) or inhibit neural activity at a brain target (also referred to as decreasing neural activity).

For example, electrical stimulation near about 50Hz (e.g., about 40Hz to about 60Hz) may induce nerve excitation (neuro-excitation), and electrical stimulation near about 130Hz (e.g., about 120Hz to about 140Hz) may induce nerve inhibition. The pulse width can range from about 1 μ s to about 1000 μ s, from about 10 μ s to about 500 μ s, or from about 80 μ s to about 120 μ s. The pulse amplitude can be between 50 μ A and about 15mA, between about 100 μ A and about 12mA, or between about 1mA and about 3 mA. In some embodiments, the IPG 110 is voltage driven and the pulse amplitude is between about 0.1V to about 10V or between about 2V to about 4V. These ranges are examples, and other ranges are possible. The stimulation parameters may be patient or disease specific and may vary during the course of treatment of the patient. For example, if the patient's body begins to encapsulate the electrodes of the electrode lead 130, the stimulation parameters may increase over time. Different stimulation parameters may induce different neurological responses in the patient, including improved or reduced beneficial effects and reduced side effects. In some embodiments, the stimulation is continuous, e.g., lasting for days, weeks, months, or years. During continuous stimulation, stimulation may be delivered intermittently. For example, stimulation may be provided for 10 minutes per hour over the course of 1 month.

In some embodiments, the IPG 110 is configured to capture and record signals from the brain or other target tissue. The captured signal may be analyzed to determine whether the signal is indicative of a disease state. For example, in some neurological disease states, the volume of the brain directly affected by the disease state can be determined by its lack of neurophysiologic activity, or conversely, by its overactive neurophysiologic activity. By performing the recording from the distal end 150 of the electrode lead 130, the neurophysiological marker signal can be recorded and analyzed by a machine learning algorithm to determine whether a disease state is present. A threshold may be set to indicate whether the neurophysiologic activity is in an "inactive" state or an "active" state. The recorded signals may also be presented to the clinician through a telemetry link with the IPG 110. A clinician may decide which electrodes of the electrode lead 130 are best suited for therapeutic stimulation. In some embodiments, the IPG 110 includes a signal processing algorithm that independently determines which electrodes of the electrode lead 130 are used to deliver electrical stimulation without clinician intervention. This may be referred to herein as closed loop stimulation.

Fig. 2 illustrates an example stimulation guide 130. The stimulation lead 130 includes a body. The body may also be referred to as a tube, pipe or conduit. The body includes a plurality of orientation indicia 156. At the distal end 150, the stimulation lead 130 includes a MEMS membrane having a plurality of electrodes 160. At the proximal end 142, the stimulation lead 130 includes a plurality of contacts 145.

At the proximal end 142 of the stimulation lead 130, the stimulation lead 130 includes one or more contacts 145. The contacts 145 may be used to establish an electrical connection between the electrodes 160 of the MEMS membrane and the IPG 110. For example, a portion of each contact 145 may be coupled with one or more electrodes 160 of the MEMS membrane via a lead wire (wires) that passes through the length of the (run) stimulation lead 130. The stimulator 122 may be coupled with the contacts 145 by a plurality of cables 120 to stimulate tissue or record physiological signals.

The distal end 150 of the stimulation lead 130 may include a MEMS membrane that includes a plurality of electrodes 160. Fig. 3A-4B illustrate the example distal end 150 and the example MEMS membrane in greater detail.

The distal end 150 of the electrode lead 130 may have a diameter of about 1mm to about 1.5mm (e.g., +/-10%). In some embodiments, the electrode lead 130 may have the same diameter along its length. A majority (e.g., about 60% to about 95%) of the electrode lead 130 may be hollow, such that a rigid mouth-cone (stylet) can provide support for the electrode lead 130 during the implantation procedure. Once the electrode guide 130 is positioned at its final target, the oral awl may be removed during surgery. The electrode lead 130 may be implanted at its target location through a surgically-prepared hole in the skull. Each hemisphere of the brain may receive at least one electrode lead 130. Each electrode guide 130 is coupled to the IPG 110 via an extension cable 120.

FIG. 3A illustrates the example distal end 150 and the example MEMS membrane 112 in more detail. The MEMS membrane 112 may be wrapped or assembled around the distal end 150 of the body 154 of the electrode lead 130 or formed as a semi-rigid cylinder that is coupled to the end of the body 154. The MEMS membrane 112 may be formed as a semi-rigid cylinder by hot rolling (rolling) the MEMS membrane 112 and back filling the lumen formed by the rolled MEMS membrane with epoxy. The MEMS membrane 112 includes a plurality of electrodes 160. The MEMS membrane 112 may also include a ribbon cable 125, the ribbon cable 125 being wrapped over the distal-most end of the MEMS membrane 112 and extending into the lumen defined by the MEMS membrane 112. The ribbon cable 125 can be coupled with one or more lead wires 162 (which can be correspondingly coupled with the contacts 145). A portion of the length of guide wire 162 wraps around the nosecone 153.

The MEMS membrane 112 may include one or more electrodes 160. As shown, the MEMS membrane 112 includes 12 electrodes-three electrodes placed around the circumference of the MEMS membrane 112 at four different longitudinal locations along the length of the electrode guide. In some embodiments, the MEMS membrane 112 may include about 6 to about 64 electrodes, about 8 to about 32, about 8 to about 24, or about 8 to about 12 electrodes. Electrode 160 may be configured as a directional electrode or an omnidirectional electrode. When the MEMS membrane 112 is formed as a cylinder, the omnidirectional electrodes may wrap primarily around (e.g., at least 80% or at least 90%) the circumferential MEMS membrane 112, and the directional electrodes may wrap (e.g., less than 80%) the planar formed cylindrical MEMS membrane 112 around only a portion of the circumference. One or more directional electrodes may be electrically coupled to form an omnidirectional electrode. For example, three distal-most electrodes 160 may be electrically coupled together to form an omnidirectional electrode at the tip of the stimulation lead 130. In some implementations, the MEMS membrane 112 may include a plurality of omnidirectional electrodes and a plurality of directional electrodes. For example, the electrodes 160 may be configured as two omnidirectional electrodes and six directional electrodes. The omnidirectional electrode may be configured as a recording electrode. The omnidirectional electrodes may be configured as stimulation electrodes. The orientation electrode may be configured as a recording electrode. The directional electrode may be configured as a stimulation electrode.

Electrical traces through the MEMS membrane 112 may couple each electrode 160 with one or more lead wires 162. The traces may thus pass under the insulating layer of the MEMS membrane 112 to the ribbon cable 125, where the traces terminate and couple with one or more lead wires 162. In some embodiments, stimulation lead 130 includes one lead wire 162 for each electrode 160. In other embodiments, the stimulation lead 130 includes fewer lead wires 162 than electrodes 160 because one or more of the lead wires 162 are electrically coupled with more than one electrode 160. For example, when the MEMS membrane 112 includes two omnidirectional electrodes and six directional electrodes, the stimulation lead 130 may include eight lead wires 162. The guide wire 162 may pass along the length of the body towards the proximal end 142 of the body. The guide wire 162 may traverse the length of the body in the body lumen. At the proximal end 142 of the MEMS membrane 112, the lead wire 162 may be electrically coupled with the contact 145.

Fig. 3B illustrates the underside of the distal end 150 of the stimulation guide 130 illustrated in fig. 3A. The MEMS membrane 112 may be initially formed as a planar membrane formed as a cylinder. This method of forming the MEMS membrane 112 may generate a connecting seam (seam) 111.

The MEMS membrane 112 may include multiple layers. In some embodiments, the MEMS membrane 112 comprises five layers. The five layers may include a first polymer layer and a first silicon-based barrier layer at least partially deposited (or otherwise disposed) on the first polymer layer. The MEMS membrane 112 may also include a first metal layer at least partially deposited (or otherwise disposed) on the first silicon-based barrier layer. The other layers may include a second silicon-based barrier layer at least partially deposited (or otherwise disposed) over the first metal layer and the first silicon-based barrier layer. The second silicon-based barrier layer may define a first plurality of vias (holes) on portions of the first metal layer. Another layer of the MEMS membrane 112 may be a second polymer layer that is at least partially deposited (or otherwise disposed) on the second silicon-based barrier layer. The second polymer layer may also define a plurality of vias. The second silicon-based barrier layer and the plurality of vias of the second polymer layer are substantially aligned to define each of the plurality of electrodes 160 and the contact pads 145 of the MEMS membrane 112.

Fig. 3C illustrates another example of the distal end 150 of the electrode lead 130 in more detail. The distal end 150 of the electrode lead 130 includes a plurality of electrodes 160. As illustrated, the distal end 150 includes four electrodes 160. The electrode 160 is configured as a cylindrical electrode (also referred to as a ring electrode). In some embodiments, electrodes 160 configured as cylindrical electrodes may emit electrical stimulation that radiates out of electrodes 160 in a substantially uniform pattern around the circumference of electrodes 160. Each electrode 160 is individually addressed (addressed) by the IPG 110 via the proximal electrical contact 145. The distal end 150 is positioned near the brain target using stereotactic techniques. One or more of the electrodes 160 may function as both a stimulating electrode and a recording electrode, or one or more of the electrodes 160 may function as only a stimulating electrode or only a recording electrode. In some embodiments, distal end 150 may comprise a combination of omnidirectional and directional electrodes.

Fig. 4A and 4B illustrate the distal end 150 of the electrode lead 130, wherein the electrode 160 is configured as an oriented electrode. As illustrated in fig. 4A, the distal end 150 includes an elliptical shaped electrode 160. The distal end 150 of the electrode lead 130 includes twelve electrodes 160. The electrodes 160 are arranged in three rows around the circumference of the distal end 150. Each column electrode 160 includes four electrodes 160. Each electrode 160 may generally cover an arc angle of about 90 degrees (e.g., +/-10 degrees) around the circumference of distal end 150. In other embodiments, the distal end 150 may include 1 to 8 columns of electrodes, each column including 1 to 10 electrodes 160. In some embodiments, each electrode 160 has a length along distal end 150 of about 0.25mm to about 2 mm. Each electrode 160 may be individually addressed by IPG 110 to ensure directional stimulation and recording. In some embodiments, an electrode 160 configured as a directional electrode is used in the brain region where there is a dense amount of neural function, such as the islet cortex. The directional electrode may ensure that the targeted electrical stimulation reaches a predetermined volume (volume). Avoiding other volumes of the brain can reduce side effects.

In some embodiments, the stimulation (characteristics of the stimulation signal and the selection of which electrodes 160 to use in the processed stimulation) is adjusted based on the biofeedback. For example, patients may recover from disease symptoms, but side effects may occur. Thus, the clinician may choose to reduce the pulse amplitude on the probe electrode until the side effects are diminished, but the beneficial effects remain. This trial and error method may provide better electrode selection, pulse frequency, pulse width and pulse amplitude. Furthermore, trial and error can update the stimulation parameters as the disease state progresses.

Each electrode 160 in a given row of distal ends 150 may be electrically coupled together to form an omnidirectional electrode. The distal end 150 also includes an orientation marker 156. The surgeon may orient the orientation marker 156 perpendicular to or along a known plane (e.g., a sagittal plane) to enable the surgeon to know the direction in which each electrode 160 faces.

Fig. 4B illustrates another example distal end 150 of the electrode lead 130. The electrode 160 of the distal end 150 is configured as an oriented electrode, as described above with respect to fig. 4A. Each electrode 160 is configured in a circular shape. In other embodiments, the electrode 160 may be square or have any other polygonal shape.

Fig. 4C illustrates a MEMS membrane (prior to forming the cylinder) with a planar configuration of electrodes 160 including redundant peripheral traces. As illustrated, a metal layer is deposited on polymer layer 305. The metal layers may include contact pads 145, traces 170, peripheral traces 314, and electrodes 160. Each peripheral trace 314 may extend around the perimeter of the associated electrode 160. Peripheral trace 314 may completely or partially surround each of plurality of electrodes 160. As illustrated in fig. 4C, peripheral trace 314 completely surrounds each of plurality of electrodes 160 by extending around the perimeter of electrodes 160. Peripheral traces 314 may be coupled with electrodes 160 at a plurality of connection points 316. Each electrode 160 may include four connection points 316. In some embodiments, each electrode 160 includes one or more connection points 316 for each edge of the electrode 160. For example, the electrode 160 may be square with four edges and one connection point 316 per edge. The connection points 316 may be placed on opposite sides of the electrode 160. In some embodiments, the contact pads 145 may also be surrounded by peripheral traces 314.

A second metal layer may be deposited on at least a portion of electrode 160. The second metal layer may include at least one of platinum, iridium oxide, or titanium.

Fig. 4D and 4E illustrate the application of a second polymer 325 (or spacer) to the first spacer 305 shown in fig. 4C. The second polymer layer 325 may include a plurality of vias 171 aligned with the electrodes 160 and contact pads 145. The silicon-based barrier layer that may be deposited on the metal layer may also include a plurality of vias aligned with the vias 171 of the second polymer layer. The second polymer 325 may be bonded to the surfaces of the first polymer layer 305 and the metal conductive layer. The second polymer 325 may be defined by photolithography (photolithographical). The resulting stack is shown in fig. 4E, where electrodes 160 and corresponding contact pads 145 are evident through vias 171, but traces 170 and peripheral traces 314 are hidden from view and electrically isolated from the external environment.

Fig. 5 illustrates a block diagram of the components of the IPG 110. The IPG 110 may include a microprocessor 205 that may coordinate and control the functions of the IPG 110. The microprocessor 205 may execute any script, file, program, application, set of instructions, or computer executable code (which is stored in the memory 250) that may cause the microprocessor 205 to perform the functions of the components of the IPG 110. The IPG 110 may include a frequency selector (selector) 210. The frequency selector 210 may select and adjust the frequency of the electrical stimulation for the electrical stimulation of the stimulation target tissue. The IPG 110 also includes a pulse width selector 215 that can select and adjust the pulse width of the electrical stimulation. For example, pulse width selector 215 may select a pulse width of the electrical stimulation in a range of between about 10 μ S and about 500 μ S. The IPG 110 may also include an amplitude selector 220, which may be configured to select an amplitude of an electrical stimulus of about 10 μ Α to about 15 mA. The amplitude selector 220 may also select whether the amplitude of the electrical stimulation is current driven or voltage driven. Electrode selector 225 may select which electrode 160 the electrical stimulation is delivered to. Electrode selector 225 may also select which electrodes 160 are used as stimulating electrodes and which electrodes 160 are used as recording electrodes. Any of the above selectors may be configured as software, scripts or applications that are executed by the microprocessor 205.

The IPG 110 also includes an analog to digital (D/a) converter 230. The D/a converter 230 is configured to output the electrical stimulation signal to the output stage 235. The output stage 235 may amplify the analog signal, change the impedance of the signal, filter, or otherwise change the characteristics of the signal. Output stage 235 may then direct the analog signal to electrode 160 as a stimulation signal. The IPG 110 may be configured to capture and record electrical signals from the target tissue. The IPG 110 includes a preamplifier 245. Preamplifier 245 amplifies the signal captured by electrode 160 and provided to IPG 110. The signal is captured as an analog signal, which is converted to a digital signal by an analog-to-digital (a/D) converter 240. The digitized signal may then be stored in memory 250. The microprocessor 205 may retrieve the signals stored in the memory 250 and send the signals to an external computer or display for review by a clinician or healthcare professional. The memory 250 may also store programs, scripts, applications and procedures that are executed by the microprocessor 205.

Fig. 6 illustrates a flow chart of a method 265 for tuning electrical stimulation delivered to a patient. The method 265 includes determining whether a symptom is present (step 270). If symptoms are present, the method 265 may include selecting a different one of the electrodes for stimulating the patient (step 285). The method 265 may also include increasing one or more characteristics of the electrical stimulation (step 280). After a predetermined amount of time, it may be redetermined whether the patient is experiencing symptoms (step 270).

As described above, the method 265 begins by determining whether the patient is experiencing symptoms (step 270). Prior to performing step 270 or after performing step 270, one or more electrode leads described herein may be implanted in or near the target location. The electrode lead may be implanted by driving the electrode lead toward the target location. The position of the electrode guide may be determined using a stereotactic procedure, an imaging procedure or by recording with the electrode guide to determine whether a characteristic signal from the target location is recorded. The target location may include a first, second, third, or fourth gyrus of the anterior island cortex; superior-anterior cerebral island; inferior-anterior cerebral island; anterior-forebrain island; posterior-anterior cerebral island; the great daodao gyrus of the hindbrain island; superior-hindbrain island, inferior-hindbrain island; a volume within a few centimeters of the brain island that projects (project) to or from the brain island. In some embodiments, a second electrode lead may be implanted at a second target location, which may be located on a contralateral side of the brain from the first target location.

The symptoms detected in step 270 may be symptoms associated with rheumatoid arthritis, crohn's disease, or any other disease described herein. At step 280, characteristics of the electrical signals generated by the IPG and delivered to the target location may be increased. In some embodiments, the characteristic is the amplitude of the electrical stimulation signal. For example, when a health professional monitors a patient for adverse effects due to increased stimulation, the amplitude may be increased over a period of time. Other characteristics may include the frequency or pulse width of the stimulation signal. If the symptoms are due to over-excitation of the target site, the frequency of the electrical stimulation signal may be set at about 40Hz to about 60 Hz. If the symptoms are due to underexcitation (under excitation) at the target site, the frequency of the electrical stimulation signal may be set at about 120Hz to about 140 Hz.

At step 285, the method 265 may further include selecting a different directional electrode through which to deliver the electrical stimulation signal. The characteristics of the electrical stimulation signal delivered to the newly selected directional electrode may be the same as the previously delivered electrical stimulation signal, or step 280 may also be performed and new characteristics that may be delivered by the newly selected directional electrode may be selected. As shown below with reference to fig. 24 and 25, new directional electrodes may be selected to direct electrical stimulation signals toward a target location and away from areas of the brain that may cause side effects.

If it is determined at step 270 that the patient is not symptomatic, a determination is made as to whether there is an adverse effect (step 275). If there are side effects, the method 265 may include selecting a different electrode (step 295) or reducing one or more characteristics of the electrical stimulation (step 290). Reducing the characteristics of electrical stimulation may reduce the effects of stimulation and side effects, as electrical stimulation may not affect a large volume of target tissue. Selecting different electrodes may reduce side effects because the new electrode may stimulate another portion of the target volume, which may control different or fewer functions. Once one or both of steps 290 and 295 are completed, the method 265 may begin after a predetermined amount of time. In some embodiments, method 265 can be repeated over minutes, hours, days, weeks, or months. The time between repeating the method 265 may depend on the amount of time it takes for the physiological performance to occur. For example, the physiological performance to be measured is a change in heart rate, which may occur almost immediately upon completion of the method 265. Other physiological manifestations, such as a reduction in tnf-a or il-6, may take hours to days to occur. If the patient does not experience symptoms at step 270 or does not have side effects at step 275, the method 265 ends. If the patient does not present symptoms at step 270 or does not have side effects at step 275, the method may continue until the optimal electrode and stimulation characteristics are selected for the patient. In some embodiments, the method 265 may continue until patient symptoms are reduced at step 270 and side effects are reduced rather than eliminated at step 275.

In some examples, after electrode 160 is placed, electrode 160 may be initially driven at a frequency of about 2Hz to about 500Hz, about 50Hz to about 400Hz, or about 100Hz to about 250Hz to reduce the activity of neurons in the target tissue. The stimulation signal applied to the electrode 160 may have a pulse width of about 10 μ s to about 500 μ s, about 10 μ s to about 400 μ s, about 10 μ s to about 300 μ s, about 10 μ s to about 200 μ s, or about 10 μ s to about 100 μ s. The current of the stimulation signal may be between about 0.1mA and about 12mA, between about 0.1mA and about 10mA, between about 1mA and about 8mA, between about 1mA and about 6mA, or between about 1mA and about 3 mA.

There are additional embodiments where the frequency is significantly lower, e.g., 50Hz, to drive and excite neural activity rather than inhibit it.

Disease states of autoimmune diseases

The systems and methods described with respect to fig. 1-6 may be used to treat any of the autoimmune diseases described herein, such as, but not limited to, those discussed below.

HLA (human leukocyte antigen) can be used to identify endogenous structures. HLA class I antigens are present on all nucleated cells of the body. HLA class II antigens are present on the surface of antigen presenting cells, such as B lymphocytes or macrophages. The genetic information for synthesizing HLR is located on chromosome 6 of the Major Histocompatibility Complex (MHC) region. T cells may play a role in autoimmune diseases. T cells were inactivated during clonal depletion in the thymus. The thymus is the superior mediastinal bivalve (double-lobed) organ, located behind the sternum. Lymphocytes that recognize endogenous HLA proliferate in the first step of clonal depletion. In the second step of clone exclusion, T lymphocytes against endogenous antigens are destroyed (negative selection). Control of the nervous system (innervation) through the thymus occurs primarily through the sympathetic (sympathically). The cell body of the efferent neural cells is located in the cervical ganglia of the sympathetic trunk.

For autoimmune diseases, the immune system is directed against endogenous structures. For example, T cells may play a role in identifying endogenous structures because regulatory T cells cannot sufficiently inhibit foreign bodies. In some cases, immunological cross-reactivity following exposure to foreign antigens (e.g., viruses or bacteria) is suspected to be the cause of autoimmune disease.

The causative factors that trigger the development of diseases of the chronic inflammatory system are not clear. Inflammatory mediators that are closely related to each other appear to play a role in initiating acute episodes and maintaining autoimmune disease. Mononuclear leukocytes (monozytes) and macrophages produce the proinflammatory cytokines interleukin 1(IL-1), interleukin 6(IL-6) and tumor necrosis factor alpha (TNF-alpha), which may help control the inflammatory process. In contrast to the effects of proinflammatory cytokines (zytokines), are anti-inflammatory mediators such as interleukin-1 receptor antagonist (IL-1ra), interleukin 10(IL-10), and interleukin 4 (IL-4). The initiation and maintenance of inflammation is mainly explained by an imbalance between pro-inflammatory and anti-inflammatory mediators. Some drugs used in immunotherapy aim to improve immune regulation (e.g., manipulate the balance between inflammation promotion and inhibition of cytokinins). This can be achieved, for example, by inhibiting the secretion of proinflammatory cytokines. While this inflammatory process may have many secondary elements, they are the major point of application in current anti-inflammatory treatment strategies.

Overview of Rheumatoid arthritis

Rheumatoid arthritis is a chronic inflammatory systemic disease that attacks the synovium of joints and causes the clinical manifestations of polyarthritis. Other organs may also be affected. The disease presents as a relapse, a progressive process, leading to joint destruction, and can lead to severe disability. The exact cause of rheumatoid arthritis is unexplained. It is an autoimmune disease in which certain endogenous tissues (e.g., articular cartilage) and connective tissues are attacked by the immune system, such as antibodies and phagocytes. This disease has a genetic predisposition. Rheumatoid arthritis is the most common inflammatory joint disease. About 0.5-1% of the world population is affected by rheumatoid arthritis. In germany, this number is estimated to be 80 ten thousand. Women are three times more likely to be affected than men. All age groups suffer from rheumatoid arthritis. The most commonly affected age group is 35 to 45 years old. According to a scientific inference, the disease can be caused by viruses or bacteria, similar to the description of the pathogenesis of rheumatoid fever (rhematoid feber). There may be a link between periodontitis disease and the development of rheumatoid arthritis. The present knowledge understands the pathogenic process as misdirected immune cells (misdirected immune cells) which enter the affected joints and produce the messenger substance promoting inflammation, the so-called cytokinin. Promoting cytokinins creates an imbalance. For example, interleukin 1(IL-1), IL-6 and tumor necrosis factor (TNF- α) are too abundant. They are responsible for the destructive inflammatory process in the joint tissue and the activation of bone-resorbing cells (e.g. osteoclasts). Through the action of cytokinins, tumor tissue, i.e. pannus, is formed on the inner lining membrane of the joint (synovium), which, after a certain time, destroys cartilage, bone and other tissues of the affected joint.

The diagnosis is performed clinically as follows: by counting and locating of painful, swollen and overheated joints; self-assessment of the patient; and passed the chemical test. Diagnosis chemical diagnoses can be made in the laboratory based on rheumatoid factors, such as ACPA status (antibodies against citrullinated protein/peptide antigens), blood sedimentation rate (ESR) and c-reactive protein (CRP). Cases of seronegative arthritis are also known, and affected persons present cases with low Rheumatoid Factor (RF), which is not sufficient for diagnosis. However, studies have shown that seropositive RF or ACPA status indicates a severe erosive course of disease with rapidly progressing joint destruction. Image generation procedures such as X-ray and Magnetic Resonance Tomography (MRT) examinations may be used to assess bone damage (erosion). Typical radiological consequences are subchondral osteoporosis, destruction of surrounding bone, ankylosis and articular deformity (buttonhole deformity, gooseneck deformity, ulnar deviation). By scintigraphy of soft tissue and bone, the distribution pattern of inflammatory activity of various joints can be delineated.

During treatment, the basal therapeutic Methotrexate (MTX) is often administered. Due to its efficacy and high tolerability, MTX is the "gold standard" for basal therapy. Additional so-called conventional basic therapeutic agents may include leflunomide, sulfasalazine, chloroquine and hydroxychloroquine, cyclosporin a, azathioprine, cortisone or cortisone-fee (cortisone-fe) anti-inflammatory agents, or combinations thereof.

The novel therapies may include antibodies, soluble receptors and antagonists directed against pro-inflammatory cytokines, such as IL-1, IL-6 of TNT-alpha. They are also known as "biologies". Directed against TNT- α are the TNF- α inhibitors adalimumab, certolizumab (certolizumab), etanercept, golimumab and infliximab. The IL-1 receptor antagonist is called anakinra, the IL-6 receptor antagonist tollizumab. B cell therapy with rituximab (monoclonal CD20 antibody) can be applied after failure of the initial TNF-a inhibitor. Due to inadequate response to the therapy and/or intolerance of the TNF- α inhibitor, the therapy may be adjusted to another TNF- α inhibitor or biologic, such as rituximab, with a different mechanism of action. Surgical treatments also exist, such as synovectomy (synovectomy), arthrectomy, arthrodesis, arthroplasty and endoscopic intubation, when severe joint changes may occur during rheumatoid disease.

Cortex of island leaf

Fig. 7 illustrates a partial cross-sectional view of a human brain. The islet cortex 300 (also referred to as the brain island 300) is a distinct brain leaf located deep in the apical lobe. Although it accounts for less than 2% of the total cortical area, it is associated with various regions of the Central Nervous System (CNS) and is involved in a wide range of functions. Based on the cellular structure of the layers in the ventral-dorsal plane, the islet cortex 300 is subdivided into three regions forming concentric layers, namely a mouth-side granule-free zone (rostral anterior agranular zone), a tail granular zone (caudorsal granular zone) and an intermediate granular zone (intercalary dynamic granular zone). Anatomically, the islet cortex 300 is separated by the ventral sulcus of the brain into a larger anterior region and a smaller posterior region. The anterior region is sometimes further subdivided into anterior and posterior rostral portions (rostral division).

Fig. 8 illustrates a block diagram of an island cortex 300. Each subsection of the island cortex 300 includes different incoming and outgoing projections. Island cortex 300 is divided into two parts: a larger anterior cerebral island 310 and a smaller posterior cerebral island 315. The anterior cerebral island 310 is subdivided by shallow trenches into three or four brachymystax 324. The posterior brain island 315 is formed by the long gyrus 330. The island cortex 300 receives afferent input from the dorsal thalamus and sensory cortex regions. Island cortex 300 interconnects the amygdala and other rim and cortical structures. Island cortex 300 also sends outgoing projections to the anterior motor cortex and ventral striatum and contains dense regional island intra-leaflet connections.

The thalamic nucleus provides a dense source of afferent input for the brain island 300. Ventral posterior bedspread (VPS) and ventral posterior inferior superior (VPI) thalamic nuclei receive afferents from vestibular nuclei and project to the parieto-insular vestibular cortex and other cortical regions. The ventral medial posterior (VMPo) thalamic nucleus receives afferent inputs from lamellar spinothalamic neurons (lamina spinothalamic neurons), which carry sensory information for nociception and thermal sensation. VMPo has an efferent projection of the posterior upper part of the brain island 300, designated as the island lobe nociception and the thermal cortex. The small cell portion of the ventral posterior medial (vpmcp) thalamic nucleus receives projections from the solitary bundle nucleus. Vpmcp includes an inner and outer subdivision (subdivisions) that have different projections. The inner portion of the vpmcp (vpmcp med) receives afferents from the rostral nucleus of the solitary tract, which receives sensory information of taste, and projects to the granular, antero-superior island cortex. The granular anterior superior islet cortex represents the major taste cortex. The side of vpmcpc (vpmcpc lat) receives projections from the oculomotor nucleus of the solitary tract, which is the termination site for sensory visceral information from the cardiovascular and gastrointestinal systems. The region of the brain island 300 that receives afferents from the oculomotor nuclei of the solitary tract is called the island visceral sensory cortex.

Island cortex 300 also receives projections from various cortical regions. The particle-free front of the brain island forms part of the orbital network and receives projections from the pre-olfactory piriform cortex, the primary and secondary taste cortex, and the primary visceral sensory island cortex. The superior posterior islet cortex includes the islet somatic association cortex (systemic associative cortex) and receives afferents from the primary somatosensory, vestibular cortex and auditory association regions.

The anterior basal portion (atrial port) of island 300 forms several strong interconnections with various edge structures, including entorhinal, perinasal, posterior orbital, temporal pole (tempopolar), cingulate cortex and amygdala. This region, known as the island blade boundary cortex, is believed to link events in the external environment to motivational status.

FIG. 9A illustrates the location of a plane 349 through the sagittal section of the patient. Fig. 9B shows a sagittal section as an MRI image 350. The MRI image 350 illustrates the relative position of the brain island 300 in the patient's brain.

Fig. 10A illustrates the location of a plane 355 through a horizontal slice of the patient. Fig. 10B illustrates a horizontal slice as the MRI image 356. MRI image 356 illustrates the relative position of brain island 300 in the patient's brain.

Fig. 11A illustrates the location of a plane 360 through a coronal aspect of a patient. Fig. 11B illustrates a coronal slice as the MRI image 361. The MRI image 361 illustrates the relative position of the brain island 300 in the patient's brain.

Fig. 12A illustrates the location of a plane 362 through the sagittal section of the patient. Fig. 12B illustrates a sagittal section as an MRI image 363. The MRI image 363 illustrates the long gyrus 330 and the short gyrus 324.

Function of island cortex

In the 50's of the 20 th century, the islet cortex 300 was considered to be a nutritive structure that controls visceral sensory and motor activity. Recent studies have shown that the islet cortex 300 functions in at least 20 independent processes, ranging from basic visceral sensation and visceral motor function to self-awareness. The role of the islet cortex 300 in the regulation of these functions is discussed and summarized in table 1 below. Functional differentiation of human islet cortex is illustrated in fig. 13.

Fig. 13 illustrates a left island cortex 300 and a right island cortex 300. The first region 372 of each island cortex 300 controls sensorimotor performance. A second region 373 of each island cortex 300 controls cognitive function. The third region 374 of each island cortex 300 controls chemosensory function. A fourth region 375 of each island cortex 300 controls social-emotional function.

Since the islet cortex 300 mediates multiple functions, it may be associated with a variety of neurological disorders, including frontotemporal dementia (frontotemporal demential), spatial neglect and neuropsychiatric disorders such as schizophrenia, depression, autism, eating disorders, anxiety, parkinson's disease and addiction.

One of the functions of island cortex 300 is self-cognition, which includes internal perception or cognition of a physiological state; knowledge of external stimuli such as taste and smell, mood, movement and temporal perception. Imaging studies have shown that the islet cortex is activated by a variety of intrinsic sensory stimuli, including heart beat, eustachian tube pinching, nasal insufflation, tactile sensation, itching, sexual arousal, hot or cold temperature, and distension of the stomach, rectum, or bladder. The brain island 300 may be activated by movement and association of movement. Looking at their own photos could activate the right island cortex, supporting the notion that this area is involved in self-cognition. In addition, the island cortex 300 may be activated in response to various emotional feelings, including maternal and romantic love, fear, anger, sadness, happiness, sexual arousal, unfairness, empathy, and trust.

The island cortex 300 may also participate in the control of motor function. Island cortex 300 may play a role in visceral motor control by affecting motor components of the autonomic nervous system as well as somatic motor control. Activation of the islet cortex 300 may also be involved in recovery of motor function following stroke. Island cortex 300 may be involved in speech coordination, separate from the areas of Broca and Wernicke. In fact, aphasia can be caused by small lesions resulting from ischemic stroke in the upper anterior cerebral island. This evidence suggests that the islet cortex 300 is an integral part of the neural circuit that regulates motor control.

In addition to sensory and motor functions, the island cortex 300 is also involved in the control of higher cognitive functions. For example, the anterior island cortex may participate in temporal perception, attention, decision making, and target oriented behavior. The anterior islet cortex contains many special spindle-shaped cells called "von Economo neurons" (VEN), which are found only in the smarter social mammals. The VEN is thought to participate in complex social cognition, decision making, and self-awareness. The VEN sends axons out of the cerebral cortex, potentially participating in the fast, intuitive decisions required for complex social interactions. The support for this concept is the discovery that these neurons are dysfunctional in frontotemporal dementia, which is associated with an unrecognized emotional impact of behavior on others.

Taken together, this evidence suggests that the islet cortex 300 can modulate sensory, motor, and cognitive functions, and link emotional states with homeostatic functions. By interfacing with the periplasmic region involved in higher cognitive function and the brainstem region responsible for visceral information delivery, the islet cortex 300 can monitor the physiological and external environment and integrate this information to produce appropriate motor and cognitive function.

Table 1: general description of island cortex function

Case study to elucidate the link between cerebral infarction and inflammatory response Activity

In the first case, one male was considered to be a child who developed hemiplegia on the right side at childhood. At age 51 he developed severe rheumatoid arthritis only on the nonparalytic side.

In the second case, patients with persistent right arm spastic paralysis after left apical leaflet removal of the surgical meningioma and subsequent irradiation. During the course of treatment, patients develop rheumatoid arthritis, resulting in swelling of seven joints of the left ankle, knee, shoulder, elbow, wrist and left hand. However, there is no representation of the right side of the body. This "protective effect" of hemiplegia is described not only for rheumatoid arthritis but also for systemic sclerosis.

In a third case, a 60 year old female showed only incomplete joint changes in the remaining 9 fingers after traumatic amputation in the 4 th finger of the left hand. In this case, a potential, unknown neuroimmune process is suspected.

Possible effects of island leaves

In one example, immunosuppression after a stroke is affected not only by the severity of the stroke, but also by its location. To investigate the effect of this location on post-stroke immunosuppression, 384 patients were examined after cerebral infarction of arterial brain mediators. Despite similar size of infarct zone, patients with infarcts in the islets had significantly higher norepinephrine levels, higher neutrophil concentrations, lower eosinophil and T-helper lymphocyte levels than patients with infarcts in other zones. Patients with islet lobe infarction also have more frequent infections in the thoracic cavity. These findings suggest that acute lesions in the islet lobe region can cause sympathetic overactivation and systemic immunosuppression. These lesions may increase the risk of infection after stroke. In another study, stimulation of islets in patients with epilepsy caused changes in heart rate and blood pressure. Although this study did not examine the effect of islet leaf stimulation on infection rate, the results suggest that the potential for island leaf stimulation affects the cardiovascular and immune systems.

As described in individual case studies, stroke can have a beneficial effect on autoimmune diseases, including rheumatoid arthritis and scleroderma. Furthermore, these effects of stroke can occur without motor deficits. These findings suggest that the resulting immunosuppression may be used to treat a variety of autoimmune and other diseases, including rheumatoid arthritis, psoriasis, psoriatic arthritis, spondyloarthritis, collagenous diseases, vasculitis, guillain-barre syndrome, crohn's disease, ulcerative colitis, IgG 4-related diseases or diseases with a potential for inflammation, such as osteoarthritis, fibromyalgia, without eliciting the side effects common to drug therapy.

A. Psoriasis disease

Psoriasis is a chronic, recurrent, benign skin disease with an increase in skin scales. It is postulated that the inflammatory response of T helper cells results in a significant reduction in the cell cycle of keratinocytes. Keratinocytes typically take 1 month to mature and migrate from the basal layer to the corneal layer, and psoriasis occurs in only 5 days. The production of epidermal cells can even be increased 30-fold.

B. Psoriatic arthritis

Psoriatic arthritis is a clinically heterogeneous inflammatory joint disease that is associated with psoriasis from the spondyloarthritis group, possibly involving the bones, joints, tendons, tendon attachments and spine. Histological or immunohistochemical examination revealed increased expression of TNF-alpha and infiltration of CD 8T-cells, macrophages.

C. Spondyloarthritis

The group of spondyloarthritic diseases show some pathophysiological and genetic similarities, in particular the association with HLA-B27. Immunopathologically, underlying spondyloarthritis is an inflammation in the bone-cartilage-boundary region and in the region of the attachment structures (enthesial structures). The interaction between the HLA-B27-allele and bacterial antigens is presumed to be responsible for spondyloarthritis due to subclinical infection or disturbance of the intestinal mucosal barrier function. However, not only the intestinal flora but also the mechanical stress is apparently pathophysiologically related to spondyloarthritis.

D. Collagen disease

Collagen disease is a systemic connective tissue disease in which different immune phenomena appear on the connective tissue and blood vessels that cause rheumatoid symptoms. The role in diagnosis is played by autoantibodies directed against nuclear material (ANA). The etiology of collagen diseases is unclear. Causes may include genetic factors, HLA antigens, hormones, psychological stress, viruses and sunlight.

E. Vasculitis

Vasculitis is an inflammatory disease of the blood vessels. It is classified according to the size and type of the affected blood vessel. Vasculitis involves non-specific symptoms such as fever, general malaise, weight loss, night sweats, fatigue and stress intolerance. Vasculitis is also related to specific symptoms such as rhinitis, sinusitis, skin rash, nervous system injury, ophthalmia, and inflammation of muscles and joints. The etiology and pathogenesis of vasculitis are unclear.

F. Guillain-barre syndrome

Guillain-barre syndrome is an acute neurological disorder with inflammatory changes in the peripheral nervous system. Guillain-barre syndrome affects the nerve roots emerging from the spinal cord and associated antero-or proximal nerve transections. The myelin sheath surrounding nerve fibers is attacked and destroyed by the immune system. The exact reason is not clear, and in some cases, prior infection may have responsibility.

G. Crohn's disease (MORBUS CROHN)

Crohn's disease is a chronic granulomatous inflammation of unknown etiology. Crohn's disease can affect every part of the gastrointestinal tract. This disease may be genetically predisposed. Several genetic factors were discovered. In at least some crohn's disease patients, there is a defect in the barrier between the intestinal lumen and the organism. Half of all patients suffer from intestinal complications such as constriction or fistula. Most patients require at least one surgical operation during their lifetime.

H. Ulcerative colitis

Ulcerative colitis is a chronic idiopathic inflammatory bowel disease characterized by clinically variable manifestations of disease activity. It exhibits several inflammatory features including immune activation, leukocyte infiltration and changes in vascular density. Many highly regulated inflammatory cytokines affect angiogenesis and are released by different cell populations, such as infiltrating immune cells and endothelial cells. Unlike crohn's disease, most of the colon is affected by inflammation, which is limited to the mucosa and submucosa.

IGG4-related diseases

IgG 4-related diseases are an increasingly recognized syndrome. With the involvement of different organs, with tumor-like swelling, lymphoplasmacytic cell infiltration, enriched IgG4 positive plasmacytic cells, increased serum IgG4 concentrations. These diseases have been documented in various organ systems, including the pancreas, bile ducts, salivary glands, kidneys, lungs, skin, prostate and orbit.

J. Osteoarthritis

Osteoarthritis is a degenerative joint disease that affects primarily the weight bearing joints in the body, especially the hips and knees. Inflammatory processes with pro-and anti-inflammatory as well as vascular proliferation and chemo-chemotactic cytokines are increasingly discussed as an important part of the pathophysiology.

K. Fibromyalgia

Fibromyalgia is characterized by hyperplastic pain, with localized changes in muscle and around joints, back pain. Fibromyalgia is also characterized by sensitivity to the sensation of pressure, fatigue; insomnia; morning stiffness; lack of concentration and power; weather sensitivity; feeling of swelling of hands, feet and face; and more symptoms. The etiology and pathogenesis of the disease are not yet explained.

Mare-Bandi syndrome

Secondary Hypertrophic Osteoarthropathy (HOA), also known as equine-bambushy syndrome, is a rare neoplastic syndrome characterized by clubbing of the fingertips, periosteal hyperplasia, synovial exudation adjacent to the joints (synovival effusions) and bronchial carcinoma. This skeletal change often precedes cancer. It is not clear why patients develop this cancer and why only a few patients develop periosteal hyperplasia. If overactivity of the islet cortex leads to synovial exudation and possibly to cancer, it can be mitigated by island cortex stimulation as described herein.

X-ray discovery

Computed Tomography (CT) is an imaging technique in radiology. By computer-based evaluation, a plurality of X-rays of the object are taken from different angles to produce a sectional image. These images may depict the weakening of the tissue. In medical terminology, tissue exhibiting a lower than expected absorption coefficient is referred to as low density (black in the CT image) and tissue having a higher attenuation coefficient is referred to as high density (white in the CT image). Bones and similar dense structures are represented in white, and air and water in black. In a CT image of the skull, the sulcus and ventricular system are depicted as black, and the skull is depicted as white. Healthy brain tissue is depicted in gray.

Fig. 14 illustrates a cranial CT image 500 of a female patient developing a right partial media infarction. The apparent black structure 501 of brain tissue is remnant infarcted along the right hemisphere of the caudate nucleus, temporal lobe, and islet lobe. After circulatory disturbance, this part of the brain dies and scars less dense than healthy brain tissue remain.

Magnetic Resonance Tomography (MRT), also known as Magnetic Resonance Imaging (MRI), produces cross-sectional images of the human body, allowing assessment of organ and many pathological organ changes. The inspection method uses the physical principle that the number of nuclei is an odd number of protons or neutrons, with an inherent angular momentum (e.g. spin). Under normal conditions, the spins are disordered. However, if a strong magnetic field is applied, the spins align the magnetic field direction in a parallel or anti-parallel manner like a compass. The nuclear spin direction alone does not produce an image. Thus, short high-frequency pulses are generated perpendicular to the magnetic field direction. After the pulse, the nuclear spins align back towards the external magnetic field and the emission energy is delivered to the environment in the form of heat. This process of reorientation is referred to as "T1 relaxation". The T1-relaxation depends primarily on the thermal conductivity of the tissue. Tissue with fast heat transfer (e.g., adipose tissue) is depicted as lighter in the T1-weighted image, while tissue with slower heat transfer is depicted as darker (e.g., liquid).

Fig. 15 illustrates a cranial MRT image 505 of the same female patient as the CT image 500 illustrated in fig. 14. The MRT image 505 is captured approximately 9 months prior to the capture of the CT image 500. In the TIRM sequence (sequence) used here, old cerebral infarction is characterized by high intensity. It showed prolonged residues of right media infarcts with material defects of right islets.

Bone scintigraphy is an imaging technique in nuclear medicine for verifying bone parts with increased bone metabolism. The physiological principle is based on chemisorption. ^99m Tc-labeled bisphosphonates such as oxicam acid accumulate on the bone surface. The extent of accumulation depends on different factors: regional blood flow, capillary permeability, and osteoblast activity. Areas with enhanced bone metabolism are depicted darker in the image and may indicate inflammatory changes, such as rheumatoid arthritis.

Fig. 16 illustrates a scintigraphic image 506 of the hand of the female patient illustrated in fig. 14 and 15. The scintigraphic image 506 illustrates the nuclide distribution at the joints of the hand 507. Image 506 illustrates the emphasis of the metacarpophalangeal joints, more to the right than to the left, which occurs simultaneously with rheumatoid arthritis. In general, fig. 14-16 illustrate that cerebral infarction can reduce disease activity in contralateral rheumatoid arthritis. Stimulation of the neural targets described herein can result in a similar reduction in the intensity of rheumatoid arthritis and other inflammatory diseases. Electrical stimulation can mimic the inhibition caused by such damage without causing resultant nerve damage.

For conventional X-ray imaging, a region of the patient's body is X-rayed from one direction. On the opposite side, the radiation is recorded with a suitable material and converted into an image. Bone absorbs more radiation than soft tissue and therefore casts a shadow that appears white on X-rays. X-ray images of healthy patients show finger bones with an almost homogenous white tone, appearing as normal mineralization with sharp boundaries. Indirect signs of rheumatoid arthritis may include demineralization near the joints, which may result in gray bone near the joint space and swelling of soft tissue. Direct signs of arthritis may include narrowing of the joint space, thinning of the edge lamellae (bone edges imprint with weaker intensity) and erosions (interruptions of the bone contour), which appear on x-rays as black holes in the bone.

Fig. 17 and 18 illustrate X-rays 510 and 515, respectively, of a hand of a 68 year old female patient that has been paralyzed from the right since birth. Twenty-one months elapsed between the receipt of X-ray 510 and X-ray 515, wherein rheumatoid arthritis of the left hand resulted in significantly more erosion and subluxation of the fourth interphalangeal joint. For rheumatoid arthritis, disease progression is expected on both sides of the body. Here missing-right hand does not show erosion. This also supports the argument for the paralytic protective effect on the inflammatory activity of rheumatoid arthritis.

Figures 19-23 illustrate X-ray images of patients with symmetric progressive psoriatic arthritis over the past few years. Following the right brain side injury in 2012, arthritis appeared on the right side with increased erosion and joint space reduction, while the patient left side did not develop increased erosion and reduction. Figures 19 and 20 show X-rays 520 and 525, respectively, of a patient's foot. Thirteen months have elapsed between the taking of X-ray 520 and X-ray 525, with psoriatic arthritis of the right foot causing significantly more erosion. Fig. 21 and 22 illustrate X-rays 530 and 535, respectively, of a patient's hand. Thirteen months passed between receiving X-ray 530 and X-ray 535, with psoriatic arthritis in the right hand causing significantly more erosion. FIG. 23 illustrates an X-ray 540 illustrating a nerve injury 545 in a patient.

Island cortex surgery target

The devices described herein are used to surgically implant at least one neurostimulation guide in at least one structure of the islet cortex to reduce the symptoms of autoimmunity and other disorders. The device may alleviate symptoms by stimulating predetermined neural targets.

The neural stimulation leads described herein may be implanted near a neural target using a stereotactic implant device. In some embodiments, surgical navigation may be assisted by CT images, MRI images, or both. The target of the neurostimulation guide may be in or near the structure of the islet cortex. The structure of the island cortex may be any of the following volumes (where the treatment effect is greatest), for example, the first, second, third or fourth gyrus of the anterior cerebral island, the superior-anterior cerebral island, the inferior-anterior cerebral island, the anterior-anterior or posterior-anterior cerebral island, the gyrus of the posterior cerebral island, the superior-posterior cerebral island, the inferior-posterior cerebral island, the volume within a few centimeters of the cerebral island that projects to or from the cerebral island, and other cerebral island volumes not mentioned herein.

As described above, one or more electrodes placed near the target region of the cerebral island may be cylindrical (e.g., omnidirectional) or segmented (e.g., directional). In both cases, it is attached to an implantable stimulator that delivers electrical stimulation to selected island lobe volumes. Cylindrical electrodes can deliver quasi-spherical and omni-directional stimulation signals to the brain volume. Segmented electrodes can deliver a more focused and directed stimulation field for brain volume. It is believed that the use of a directional stimulation field may reduce the occurrence of side effects because a smaller portion of the brain may be stimulated.

Fig. 24 illustrates an example atlas (atlas) for stereotactic positioning of a human brain 600. Atlas 600 illustrates the relative positions of electrodes 160. Electrode 160 may be a directional electrode. The directional electrode 160 is placed in the plate 29 at a distance Fp 15,5 of the atlas 600. The directional electrodes 160 are placed in the island cortex 300. A potential field 910 is applied to the tissue from the directional electrode 160. The directional electrode 160 points in the upper right direction (w/relative to the atlas) for that particular anatomy. Directing the potential field 910 in this direction may reduce side effects because the potential field 910 is directed away from sensitive structures, such as the putamen (putamen) 915.

Fig. 25 illustrates an example atlas for stereotactic use in a human brain 650. Atlas 650 illustrates the relative positions of electrodes 160. Electrode 160 may be a directional electrode. The directional electrode 160 is placed in the plate 27 at a distance Fp 3,0 of the atlas 650. The directional electrode 160 is placed in the island cortex 300 from which a potential field 910 is applied to the tissue from the directional electrode 160. For this particular anatomy, the electrode 160 points in the upper right direction (relative to the atlas). The directional electrode 160 may direct the potential field 910 away from sensitive structures such as the lenticular nucleocapsid 915, which may reduce side effects.

Various embodiments of microelectrode devices have been described herein. These embodiments are given by way of example and do not limit the scope of the present disclosure. The various features of the embodiments that have been described may be combined in various ways to produce several additional embodiments. In addition, while the various materials, dimensions, shapes, implantation locations, etc. used in the disclosed embodiments have been described, other materials, sizes, shapes, implantation locations, etc. than those disclosed may be utilized without exceeding the scope of the present disclosure.

Devices described herein as acute (acute) or chronic (chronic) may be used acutely or chronically. These devices may be implanted at these periods, such as during surgery, and then removed. These devices may be implanted for multiple sustained extended periods or indefinitely. Any device described herein as chronic may also be used acutely.

The present disclosure is not limited in terms of the particular embodiments described in the present application, which are intended to be exemplary in all respects. Modifications and variations may be made without departing from the spirit or scope of the disclosure. Functionally equivalent methods and apparatuses may be within the scope of the invention. Such modifications and variations are intended to fall within the scope of the appended claims. The subject matter of the present disclosure includes the full scope of equivalents to which the invention is entitled. The present disclosure is not limited to particular methods, agents, compound compositions, or biological systems that may vary. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

With respect to the use of substantially any plural or singular terms herein, the plural may include the singular or the singular may include the plural as appropriate to the context or application.

In general, the terms used herein, and especially in the appended claims (e.g., bodies of the appended claims), are generally intended as "open" terms (e.g., the term "including" should be interpreted as "including but not limited to," the term "having" should be interpreted as "having at least," the term "includes" should be interpreted as "includes but is not limited to," etc.). Claims directed to the subject matter may include the use of the introductory phrases "at least one" and "one or more" to introduce claim recitations. However, the use of these phrases should not be construed to imply that: the introduction of a claim recitation by the indefinite article "a" or "an" limits any particular claim containing such introduced claim recitation to embodiments containing only one such recitation, even if the same claim includes the introductory phrases "one or more" or "at least one" and indefinite articles such as "a" or "an" (e.g., "a" and/or "an" should typically be interpreted to mean "at least one" or "one or more"); the same holds true for the use of definite articles used to introduce claim recitations. In addition, even if a specific number of an introduced claim recitation is explicitly recited, such recitation may mean at least the recited number (e.g., the bare recitation of "two recitations," without other modifiers, means at least two recitations, or two or more recitations). Additionally, in instances where a convention analogous to "at least one of A, B and C, etc." is used, in general such a construction would include, but is not limited to, systems having A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B and C together, etc. In instances where a convention analogous to "A, B or at least one of C, etc." is used, in general such a construction would include, but is not limited to, systems having A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B and C together, etc. Any disjunctive and/or phrase presenting two or more alternative terms (whether in the description, claims, or drawings) is contemplated as including the possibility of one of the terms, any one of the terms, or both terms. For example, the phrase "A or B" includes the possibility of "A" or "B" or "A and B".

Terms of degree such as "about" or "substantially" include the number identified and a range of +/-10% from the number identified. References to "or" include exclusive or inclusive or examples.

In addition, while various features or aspects of the invention are described in terms of Markush groups (Markush groups), the disclosure of the present application is also described in terms of any individual member or subgroup of members of the Markush group.

Any range disclosed herein also encompasses any and all possible subranges and combinations of subranges. Any recited range can be readily identified as fully descriptive and as enabling the same range to be subdivided (break down) into at least equal halves, thirds, quarters, fifths, tenths, etc. By way of non-limiting example, each range discussed herein can be readily subdivided into a lower third, a middle third, and an upper third, etc. Language such as "up to," "at least," "greater than," "less than," and the like includes the recited number and refers to a number of ranges that may then be subdivided into subranges as discussed above. Finally, a range includes each individual member.

One or more of the techniques described herein, or any portion thereof, may be implemented in computer hardware or software, or a combination of both. These methods may be implemented in a computer program using standard programming techniques conforming to the methods and illustrations described herein. Program code is applied to input data to perform the functions described herein and generate output information. The output information is applied to one or more output devices, such as a display monitor. Each program may be implemented in a high level procedural or object oriented programming language to communicate with a computer system. However, the programs can be implemented in assembly or machine language, if desired. In any case, the language may be a compiled or interpreted language. In addition, the program may run on an application specific integrated circuit programmed for that purpose.

Each such computer program may be stored on a storage media or device (e.g., ROM or magnetic diskette) readable by a general or special purpose programmable computer for configuring and operating the computer when the storage media or device is read by the computer to perform the steps described herein. Computer programs may also reside in a cache or main memory during program execution. The analysis, pre-processing, and other methods described herein may also be embodied as a computer-readable storage medium configured with a computer program, where the storage medium so configured causes a computer to operate in a specific and predefined manner to perform the functions described herein. In certain implementations, the computer-readable medium is tangible and substantially non-transitory in nature, for example, such that the recorded information is recorded in a form other than solely as a propagated signal.

In some implementations, the program product may include a signal bearing medium. The signal bearing medium may include one or more instructions that when executed by, for example, a processor, may provide the functionality described above. In some embodiments, signal bearing media may encompass computer readable media such as, but not limited to, hard disk drives, Compact Discs (CDs), Digital Video Discs (DVDs), digital tapes, memory, and the like. In some embodiments, a signal bearing medium may encompass recordable media such as, but not limited to, memory, read/write (R/W) CDs, R/W DVDs, and the like. In some embodiments, a signal bearing medium may encompass communication media such as, but not limited to, digital or analog communication media (e.g., fiber optic cables, waveguides, wired communications links (links), wireless communication links, etc.). Thus, for example, the program product may be conveyed by an RF signal bearing medium where the signal bearing medium is conveyed by a wireless communication medium such as one conforming to the IEEE 802.11 standard.

Any signal and signal processing techniques may be digital or analog in nature, or a combination thereof.

While certain embodiments of the present disclosure have been particularly shown and described with reference to preferred embodiments thereof, various changes in form and details may be made therein without departing from the scope of the present disclosure.

Claims (20)

1. A device for treating an autoimmune disease, wherein the device comprises a guide and a stimulator:

the guide has a MEMS membrane comprising:

a plurality of electrodes;

a plurality of peripheral traces at least partially surrounding each of the plurality of electrodes; and

at least two connection points coupling each of the plurality of peripheral traces with a respective one of the plurality of electrodes; and is

The stimulator generates an electrical signal, wherein:

the stimulator and the lead are to be implanted in a patient;

the guide is to be driven toward a first target location of a patient, wherein the first target location comprises one of a first, second, third, or fourth gyrus of the anterior island cortex; superior-anterior cerebral island; inferior-anterior cerebral island; anterior-forebrain island; posterior-anterior cerebral island; the great island of the hindbrain island; superior-posterior cerebral island; or inferior-posterior cerebral island; and is

An electrical signal is to be delivered to a first target location through at least one of the plurality of electrodes.

2. The apparatus of claim 1, further comprising:

the second guide is driven relative to the first target position toward a second target position located on a contralateral side of the patient.

3. The device of claim 1, wherein at least one of the plurality of electrodes is a directional electrode.

4. The apparatus of claim 3, further comprising:

recording neural activity from the target location; and

a portion of the plurality of electrodes is selected for delivering an electrical signal based on the recorded neural activity.

5. The apparatus of claim 1, further comprising:

detecting the presence of symptoms of an autoimmune disease; and

increasing the characteristics of the electrical signal.

6. The apparatus of claim 5, wherein the electrical signal is characterized by at least one of an amplitude, a frequency, and a pulse width.

7. The apparatus of claim 1, further comprising:

detecting the presence of a side effect caused at least in part by the electrical signal; and

reducing the characteristics of the electrical signal.

8. The apparatus of claim 1, further comprising:

determining that neural activity of the target region is below a predetermined threshold; and

an electrical stimulus having a frequency of 120Hz-140Hz is applied.

9. The apparatus of claim 1, further comprising:

determining that neural activity of the target region is above a predetermined threshold; and

an electrical stimulus having a frequency of 40Hz-60Hz is applied.

10. The apparatus of claim 1, wherein at least one of the plurality of electrodes is an omnidirectional electrode.

11. The apparatus of claim 10, wherein the omnidirectional electrode is a recording electrode.

12. The device of claim 1, wherein the MEMS membrane comprises:

a ribbon cable extending from a distal end of the MEMS membrane and into a cavity defined by the MEMS membrane.

13. The device of claim 12, wherein the ribbon cable comprises a plurality of contact pads, wherein each of the plurality of peripheral traces is coupled to one of the plurality of contact pads.

14. The device of claim 1, wherein each of the plurality of electrodes comprises a second metal layer.

15. The apparatus of claim 14, wherein the second metal layer comprises at least one of platinum, iridium oxide, or titanium.

16. The apparatus of claim 1, further comprising:

an electrical signal having a frequency of 2Hz-500Hz is generated.

17. The apparatus of claim 1, further comprising:

an electrical signal having a pulse width of 10 mus-500 mus is generated.

18. The apparatus of claim 1, further comprising:

an electrical signal is generated with a current of 0.1mA-12 mA.

19. The apparatus of claim 1, further comprising:

selecting a different one of at least one of the plurality of electrodes for delivering the electrical signal; and

an electrical signal is delivered to a first target location through a different one of at least one of the plurality of electrodes.

20. The device of any one of claims 1-19, wherein the autoimmune disease comprises at least one rheumatoid arthritis; psoriasis; psoriatic arthritis; spondyloarthritis; collagen diseases; vasculitis; guillain-barre syndrome; crohn's disease; ulcerative colitis; igg 4-related diseases; osteoarthritis; fibromyalgia; and equine-bambushy syndrome, and treating autoimmune disease with the electrical signal.

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